This proposed training program builds on the successes and lessons of the previous 14 years to meet the new emerging and evolving challenges of a maturing HIV epidemic in southern Africa, the epicenter of the global HIV pandemic. The 125 long-term and 186 short-term trainees of the current program continue to have a major impact through their leadership roles globally and locally, as their research generates new knowledge in areas such as HIV pathogenesis in acute HIV infection, new prevention technologies (including antiretrovirals to prevent breastfeeding transmission, vector-based HIV vaccines and antiretroviral microbicides), and new approaches to treating HIV-TB co-infection. The trainees have published 894 peer- reviewed papers including several in high impact journals like Science, Nature and the Lancet. The emergence of HIV-associated drug-resistant tuberculosis (TB), the implementation of the largest AIDS treatment program in the world and the dire need for evidence to guide decision-making as South Africa transitions from its denialist past to a politically enlightened future under a new Minister of Health, have created a set of new challenges and opportunities for the next cycle of this program. Building on the substantive science base, extensive research infrastructure and local expertise created through this program, the rich tapestry of in-country AIDS and TB studies, the strategic collaborations within and outside South Africa, and the new opportunities to leverage funding from other agencies, the proposed program will continue to identify trainees with the most potential, offer them high quality training both in South Africa and the USA and provide them with ongoing support to create a critical mass for an effective response to the HIV and TB epidemics in southern Africa. The proposed program sets about this task well armed with the most valuable lessons learnt in the past decade such as the importance of long-term in-country mentorship, ongoing training in grant writing and administration, strategic partnering to maximize training opportunities, recruitment of candidates in consultation with local productive research groups and the value of having joint USA and South African faculty in raising the standard of in-country training. Guided by the ongoing assessment of training priorities and with careful oversight from a balanced US- SA Training Advisory Committee, that includes several previous trainees who are now senior investigators, we will continue to provide, as appropriate, a variety of short-to-medium, and long-term training opportunities in the USA, South Africa, Swaziland, Namibia and Lesotho. The emphasis of the program in the next cycle is to i) address critical training gaps in existing HIV and TB centers of research excellence in South Africa to meet the new emerging challenges in the HIV epidemic, ii) provide support and mentorship for young investigators, especially medical students, and iii) provide the training critical to the efforts of South African AIDS research to transition from the current reliance on multicenter studies to a more sustainable balanced portfolio with increased levels of investigator-initiated research. The goal is to strengthen and expand the existing number of independent HIV and TB research teams in southem Africa; strengthen local capacity to assume more of the region's training needs and developing the skills needed to assist policy makers with evidence to implement and monitor the scale-up of HIV/AIDS prevention and treatment programs. PUBLIC HEALTH RELEVANCE: This program is a critical training resource for strengthening the institutional science base for undertaking pivotal HIV and TB research in the epicenter of the HIV pandemic to enhance responses to the HIV and TB epidemics in South Africa, Swaziland, Lesotho and Namibia